Systematic reassessment reveals new pairings of the atypical chemokine receptors ACKR2, ACKR3 and ACKR4 with chemokines
Atypical chemokine receptors (ACKRs) form a subfamily of four enigmatic chemokine receptors (ACKR1-4) unable to trigger G protein-dependent signalling in response to chemokines. However, they do play a crucial regulatory role in chemokine biology by capturing, scavenging or transporting chemokines, thereby regulating their availability and signalling through classical chemokine receptors. ACKRs add thus another level of complexity and fine-tuning to the already highly intricate chemokine-receptor interaction network. In this study, we undertook a systematic screening program aiming at reassessing the agonist activity towards ACKR2, ACKR3 and ACKR4 of the 43 human chemokines (24 CCL, 16 CXCL, 2 XCL chemokines and CX3CL1) and 2 viral chemokines (vCCL1 and vCCL2) by monitoring β-arrestin recruitment using highly sensitive Nanoluciferase complementation-based assays (NanoBiT and NanoBRET). Our systematic analysis identified the inflammatory CXC chemokine CXCL10, previously reported to bind to CXCR3 only, as a new strong agonist ligand for ACKR2. We also revealed CCL20 and CCL22 as new full and partial agonist ligands for ACKR4 and the viral broad-spectrum antagonist chemokine vCCL2/vMIP-II encoded by the Kaposi sarcoma-associated virus HHV-8 as an agonist chemokine of ACKR3. Altogether, these findings shed new light on the complexity of the chemokine network and expand the panel of ACKR ligands and functions. It also highlights the need for a systematic reassessment of chemokine-receptor pairing, as important interactions may remain unexplored.


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